Phase I Biologic Endpoints and Surrogate Markers

Phase I trials are small studies aimed at finding the optimal dose of a drug using schedules determined from preclinical models. In conventional trials with cytotoxic agents, maximal tolerated dose (MTD) is often used to define the optimal dose rather than using the dose that has a quantifiable therapeutic effect. The dose of the agent is escalated in cohorts of three to six patients until there is unacceptable toxicity in two or more patients. The design of phase I trials is based on the assumption that the efficacy and toxicity of the drug increases as the dose increases and that the mechanism of toxicity and tumor effect are the same. Pharmacoki-netic studies are included in Phase I trials but are not required to determine the optimal dose of a cytotoxic agent.

Due to their selective effect, targeted agents have the potential to achieve maximum biologic effect with minimal side effects. Therefore, the optimal dose in Phase I trials may need to be defined by a biologic endpoint rather than toxic-ity. Their wider therapeutic ratio may in some cases make it difficult to determine the MTD. Furthermore, the mechanisms of toxicity and biologic effect may differ, and therefore, MTD cannot be used to define the optimal dose. Conversely, others contend that unless the MTD and intratumoral phar-macodynamics of the novel agent are determined in Phase I and II clinical trials, Phase III trials run the risk of inadequate dosing and suboptimal target inhibition.2

Consequently, biologic endpoints in tumor and surrogate tissue rather than dose-limiting toxicity are often used to define the optimal dose of targeted agents for subsequent clinical trials. This characterization requires a biologic understanding of the target, a specific and reproducible assay for target inhibition, knowledge of the distribution of the target in the tissues of interest, accessibility of the appropriate tissue, and demonstration that the tissue is a valid surrogate for the tissue of interest. Phase I trials with targeted agents aim to define the dose or concentration of a drug that

TABLE 5.7. Antiangiogenesis therapies.


Mechanism of action


Major toxicity

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